An energy-dense diet high in fat, refined sugar and providing excess calories relative to energy expenditure that is typical of Western diets has been associated with an increased risk of prostate cancer (CaP). Increased intake of lycopene-rich foods, such as cooked tomatoes, is associated with a decreased risk of CaP. Insulin-like growth factor-I (IGF-I) is a potent mitogen that has been implicated as a critical factor in the development of CaP. The pro-oncogenic role of IGF-1 has been extensively demonstrated in both in vitro studies and in animal models of cancer as well as in human epidemiological cohorts. Serum IGF-I is regulated by caloric intake in both human and animal models and it has been proposed that certain nutrients that may prevent CaP, in particular lycopene, also modulate IGF-I levels. Our preliminary data suggest that men at high risk for CaP who adopt a very low fat, high fiber diet under residential conditions, have reduced serum IGF-1 levels and their sera have decreased mitogenicity for CaP cells in vitro. We have also demonstrated that in CaP xenograft-bearing SCID mice, a low-fat diet reduces serum IGF-I and leads to decreased mitogenicity of sera as well as to a marked reduction of tumor size and increased tumor apoptosis, when compared to mice fed a high fat, isocaloric diet. In addition, we studied TRAMP mice, a transgenic model of CaP (transgenic for SV40T antigen with a probasin promoter), and showed that decreasing caloric intake by 20% lowered serum IGF-I levels and decreased tumor incidence and severity. IGF-I infusion to these diet-restricted TRAMP mice restored serum IGF-I to ad-lib levels and caused an increase in tumor incidence similar to that seen in the ad-lib group. These studies led us to theorize that IGF-I is an important oncogenic circulating molecule, whose levels can be modulated by dietary composition. We hypothesize that that bioavailable IGF-I within the microenvironment of prostate epithelial cells in vitro is a major determinant of CaP development and progression. Therefore, modulation of IGF-I levels by nutritional factors may be an important potential therapeutic target for determination of CaP risk and progression. Our proposed studies will determine if dietary fat and/or lycopene regulate serum-bioavailable IGF-I in a manner that determine the development of CaP. Our specific aims are to: 1) Establish the effects of modulating dietary fat content from 42 to 12% on serum IGF-I and the concurrent progression of CaP in TRAMP mice and determine whether infusion of IGF-I is capable of reversing any reduction of tumor progression in the low-fat-fed group. 2) Examine the effects of genetically lowered serum IGF-I on the progression of CaP in LID mice, in which the liver IGF-I gene has been selectively deleted using Cre-Lox technology and in whom circulating IGF-I levels are 25% of normal, mated with TRAMP mice. 3) Determine if a high-fat diet modulates CaP progression and/or serum IGF-I in the LID-TRAMP model to assess the linkage between serum IGF-I, dietary fat and CaP. 4) Examine the relationships of dietary lycopene and fat in modulating CaP progression and/or serum IGF-I in the TRAMP and LID/TRAMP models. We will determine the relative importance of free (bioavailable) IGF-I as compared to total IGF-I (which is bound to IGFBPs) in the development of CaP by developing new, specific assays for mouse free and total IGF-I, IGFBP-3 and IGFBP-1 Our studies will provide definitive information regarding the role of IGF-I as an important nutritionally regulated serum marker for CaP risk and progression and will allow the design of logical strategies to determine of the efficacy of dietary interventions in CaP prevention and treatment in humans.